Formulation and manufacturing process for Coenzyme Q10 soft gel capsules

ABSTRACT

A soft gelatine capsule formulation improved manufacturing of Coenzyme Q10, comprising Coenzyme Q10 in a thixotropic gelatine carrier capable of admixing without heating with Coenzyme Q10, and capable of keeping Coenzyme Q10 in suspension at ambient temperature.

This is a Continuation of U.S. application Ser. No. 10/368,260 filed onFeb. 18, 2003, which is a Continuation-In-Part of U.S. application Ser.No. 09/873,156 which was filed Jun. 1, 2001, now abandoned, that in turnclaims priority benefit of U.S. Provisional Application Ser. No.60/263,953 filed Jan. 24, 201, the contents of which are incorporatedherein in their entirety.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to a composition and process of manufacturingCoenzyme Q10 with improved human absorption characteristics in athixotropic gelatin carrier capable of admixing without heating theCoenzyme Q10, and capable of suspending Coenzyme Q10 in a uniformdispersion.

2. Background go of the Invention

Coenzyme Q10 (CoQ10 or Ubiquinone) is a large molecular weight (863.63grams) lipid compound that is produced in the liver and perhaps otherbody organs. The total human body content is estimated to be 1.4 to 1.8grams, depending on the age and the physical fitness of the individual.Although CoQ10 is found in the mitochondria and other organelles ofevery living cell, it appears to be most abundant in tissues with a highnumber of mitochondria and a high level of metabolic activity. Forexample, there is approximately 4 mg of CoQ10 in the heart tissues, andabout 1000 mg in the skeletal muscle. The blood acts as a CoQ10reservoir and transport media between endogenous CoQ10 synthesis in theintestinal liver, exogenous CoQ10 absorption from digested foodsubstances in the intestinal tract, and the body cells. Endogenoussynthesis appears to be responsible for 56 percent and exogenous sourcesfor 44 percent of the body's CoQ10 requirements. These numbers arecurrently being studied and endogenous CoQ10 synthesis may besignificantly deficient in the elderly. Furthermore, certain diseasestates, such as mitochondrial myopathy, and prescription drugs, such ascholesterol-lowering statin drugs, seem to deplete the endogenous CoQ10levels in the body. These deficiencies are not related to the totalcaloric intake, but rather to the vitamin content of ingested foods asthe body requires multiple vitamins for the synthesis of CoQ10.

CoQ10 requirements of the body are also variable between individuals andare dependent on age, physical activity, and disease. It is estimatedthat the body CoQ10 utilization is between 5 and 9 mg per day.Intercellular CoQ10 is required for the synthesis of energy andtherefore essential for life. Energy synthesis occurs in themitochondria, where CoQ10 provides an electron for the electrontransport chain in the cytochrome system, in which adenosinetriphosphate (ATP) is synthesized. As CoQ10 gives up an electron for theATP synthesis, it gets oxidized. If CoQ10 is used as an antioxidant, itgets oxidized and is no longer available to provide electrons andfunction in the synthesis of ATP. Under conditions of high metabolicstress, endogenous sources may become inadequate to meet the body'sCoQ10 requirement for ATP synthesis. Under such conditions, dietaryCoQ10 supplementation has been shown to be an effective source. CoQ10has been used to treat heart failure, chronic fatigue and patients withpsoriasis and planter warts. In all cases, it has been found that theimproved soft gel formulation, at doses of 30-100 mg/day of CoQ10, havebeen proven to be superior to commercially available 60 mg dry powdercapsules, and existing 100 mg/day CoQ10 soft gel formulations.

An appropriate CoQ10 dosage for a normal individual compared to thedosage necessary for a diseased individual has been difficult toascertain. Recommended doses of 10 to 30 mg/day were found to beineffective for patients with significant CoQ10 deficiencies. In thepast 15 years, it has become generally accepted that poor intestinalabsorption of certain CoQ10 formulations limits their effective use. Forthis reason, 50 and 150 or even 200 mg tablets or capsules arecommercially available to the consumer, at a considerable higher cost,the main cost driver being the CoQ10.

Folkers et al. (U.S. Pat. No. 4,824,669) addresses a soft gel capsulewith CoQ10 and at least one vegetable oil. This formulation wasdetermined to increase blood CoQ10 levels to 2.5 μg/ml compared to 1.6μg/ml for an equivalent 100 mg dose of dry powder CoQ10. Many differentCoQ10 formulations have appeared which are claimed to increaseintestinal absorption. However, intestinal absorption data, collectedunder near basal conditions, which compare CoQ10 alone in oil with drypowder CoQ10, are inconclusive.

SUMMARY OF THE INVENTION

The present invention comprises a formulation of Coenzyme Q10 forimproved manufacturing of soft gelatine capsules containing CoenzymeQ10.

According to the present invention, a preferred soft gel formulationincludes Coenzyme Q10, Vitamin E (mixed tocopherols) added as afunctional antioxidant, and a thixatropic gelatin carrier which has theability of enhancing the solubility and stability of the activeingredient and provides for better absorption thereof in humans. Anadditional ingredient, an antioxidant, either from natural or syntheticsources, can be added in order to prepare a potent combinationantioxidant formulation. The preferred soft gel Coenzyme Q10 formulationis administered twice a day in dosages of about 30 mg, thereby reducingthe Coenzyme Q10 cost while producing the desired retained Coenzyme Q10in the human body.

Other features and advantages of the present invention will become moreapparent from the following detailed description, which illustrate,byway of example, the principles of the invention.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The present invention utilizes a gelatine carrier with thixatropicproperties and substantial capacity to suspend active ingredients in auniform dispersion. The carrier composition used in the presentinvention is described in U.S. Pat. No. 6,365,181 (issued to Matthews),and is a thixatropic carrier gel comprising a homogeneous dispersion ofviscosity modifiers and surface active agents in vegetable oil. When thecarrier composition is agitated, such as by slow stirring, it becomesfluid, and when the agitation is stopped, it becomes a highly viscoussemi-solid. Active agents are easily admixed with the carriercomposition by stirring and high loadings of the active agents can beused to make a stable uniform dispersion within the carrier compositionbecause the composition becomes semi-solid when stirring is stopped.

As described in the Matthews patent, the components of the carriercomposition include from about 84% to 95% of a vegetable oil, from about1% to 9% of a viscosity modifier, and from about 1% to 15% of a surfaceactive agent such that the total amounts to 100%. Other details of thethixatropic gelatine carrier used in the present invention are describedin the Matthews patent, and are incorporated herein by reference.

The unique formulation of the present invention involves the followingsequence of ingredients and process methodology:

-   -   (A) Heat the thixatropic gelatine carrier to a temperature of        about 25° C. to about 35° C. (preferably about 27° C. to about        30° C.);    -   (B) Simultaneously add in a container under vacuum the following        ingredients to the pre-heated thixatropic gelatine carrier:        Coenzyme Q10, Vitamin E, and if desired, additional antioxidant        in compatible form, the vacuum being to prevent oxidation of any        of the ingredients;    -   (C) Blend and continuously stir all of the ingredients into a        mixture;    -   (D) Cool the mixture to a temperature of about 23° C. to 28° C.        (preferably about 25° C.);    -   (E) Mix the mixture within the container under a blanket of        nitrogen gas to prevent oxidation of any of the ingredients; and    -   (F) Encapsulate the mixture in a soft gel capsule.

If the cooled mixture sits for any length of time under its blanket ofnitrogen before encapsulation, re-mix under the blanket of nitrogen toassure a homogenous mixture for encapsulation.

Typical amounts of ingredients per capsule are:

-   -   −50 to 500 mg of the thixatropic gelatine carrier, described        above;    -   −30 to 100 mg of Coenzyme Q10;    -   −10 to 100 IU Vitamin E; and if desired    -   −0.5 to 500 mg of additional antioxidant.

The bioavailability or intestinal absorption of CoQ10 has been a majorcontroversy in the international CoQ10 research community. Previous dataindicate that only 1 to 3% of a dry powder CoQ10 formulation is absorbedthrough the lacteals in the intestines and appears in the blood over atwelve hour interval. In general, blood levels of 1.2 to 1.6 μg/ml havebeen reported, when taking 30 to 60 mg/day dry powder CoQ10 formulationfor 30 days. It has been reported that when a dry powder CoQ10formulation is taken with a fat, such a peanut butter, steady-stateblood levels of 2.0 to 2.8 μg/ml are measurable. Multiple clinicaltrials were conducted in the United States and Europe using the Folkers(U.S. Pat. No. 4,824,669) soft gel. With a dosage of 100 mg/day multipleinvestigators have reported group mean blood levels of 2.3 to 3.5 μg/mldepending on the laboratory conducting the measurement.

The present invention's 30 mg CoQ10 soft gel formulation of CoQ10provides approximately 50%, and with two capsules 100%, of the dailyCoQ10 requirements of a normal sedentary individual. It would take atleast three of the dry powder 30 mg CoQ10 capsules to produce the sameeffects as one of the present invention in 30 mg soft gel form, and sixof the dry powder 30 mg CoQ10 capsules to produce the same effect as twoof the present invention 30 mg CoQ10 soft gel capsules.

Regardless of the absorption mechanism, the significantly higher basalblood CoQ10 levels (167%) and the 273% greater absorption rate found instudies, establish that the present invention soft gel formulation isindeed a superior product to the dry powder CoQ10 formulations. This maybe especially true for those individuals whose daily CoQ10 requirementis elevated due to: high physical activity; a need for CoQ10 as anantioxidant; or active disease associated with known CoQ10 deficiencies.

Cellular CoQ10 content is a function of the number and quality of thecellular mitochondria. For example, the failing heart muscle has 2.2 μgCoQ10 per mg tissue and a blood CoQ10 deficiency (0.3-0.5 μg/ml). Thenormal conditioned heart has 6.3 μg/gm in its tissue, and a low basalblood level (0.5-0.6 μg/ml). These results indicate that supplementalCoQ10 enters the cell. This observation has also been reported forskeletal muscles of trained and non-trained athletes.

The subjective and objective responses to supplemental CoQ10 in thenormal individual appear more rapidly compared to that of the physicallyunfit or the diseased individual with a CoQ10 deficiency. The mostprobable reason for this observation is that the metabolic machinery(mitochondria) is viable in the non-diseased normal volunteer, whereasthe mitochondria are atrophied in the cells of de-conditioned anddiseased individuals. Therefore, it takes time in the diseasedindividual to build up the mitochondria to a more normal activity leveland to normalize their distribution in the organ system involved.

Thus, there has been described a novel CoQ10 formulation and method offormulation, which fulfill all the objects and advantages soughttherefor. Many changes, modifications, variations and applications ofthe subject invention will become apparent to those skilled in the artafter consideration of the specification. All such changes,modifications, alterations and other uses and applications which do notdepart from the spirit and scope of the invention are deemed to becovered by the invention which is limited only by the claims thatfollow.

1. A composition comprising Coenzyme Q10 in combination with anantioxidant in a thixatropic gelatine carrier for manufacturing soft gelcapsules at a temperature of about 27° C. to about 30° C. containing astable uniform suspension of Coenzyme Q10.
 2. A soft gel capsulecomprising Coenzyme Q10 and a thixatropic gelatine carrier.
 3. The softgel capsule of claim 2, wherein the thixatropic gelatine carrier is asemi-solid at a temperature of about 23° C. to about 28° C. and becomesfluid when stirred.
 4. The soft gel capsule of claim 2, wherein thethixatropic gelatine carrier comprises: from about 84% to about 95%vegetable oil selected from the group consisting of soybean oil,rapeseed oil, palm oil, and cotton seed oil; from about 1% to about 9%of a viscosity modifier selected from the group consisting of a glycerylpalmito stearate and glyceryl behenate; and from about 1% to about 15%of a surface active agent comprising polyglyceryl oleate.
 5. The softgel capsule of claim 2, wherein the amount of Coenzyme Q10 in the softgel capsule ranges from 8 to 40% by weight.
 6. A process ofmanufacturing a soft gel capsule comprising Coenzyme Q10, said processcomprising the steps of: (a) stirring a thixatropic gelatine carrieruntil the thixatropic gelatine carrier is liquefied; (b) adding CoenzymeQ10 to the liquefied carrier to form a mixture; and (c) encapsulatingthe mixture in a soft gel capsule.
 7. The process of claim 6, whereinthe thixatropic gelatine carrier comprises: from about 84% to about 95%vegetable oil selected from the group consisting of soybean oil,rapeseed oil, palm oil, and cotton seed oil; from about 1% to about 9%of a viscosity modifier selected from the group consisting of a glycerylpalmito stearate and glyceryl behenate; and from about 1% to about 15%of a surface active agent comprising polyglyceryl oleate.
 8. The processof claim 6, further comprising the step of heating the thixatropicgelatine carrier from about 27° C. to about 30° C. prior to the additionof the Coenzyme Q10.
 9. The process of claim 6, wherein 30 to 100 mg ofthe Coenzyme Q10 are in each capsule.
 10. The process of claim 6,wherein the mixture is cooled from about 23° C. to 28° C.
 11. Theprocess of claim 6, wherein 50 to 500 mg of the thixatropic gelatinecarrier is in each capsule.
 12. A soft gel capsule, prepared by aprocess comprising the steps of: (a) heating a thixatropic gelatinecarrier to a temperature that liquefies the carrier; (b) blending theheated thixatropic gelatine carrier and Coenzyme Q10; (c) cooling theblended mixture to a temperature, thereby causing the mixture to form aviscous semi-solid; and (e) encapsulating the mixed, cooled mixture in asoft gel capsule.
 13. The soft gel capsule prepared by the process ofclaim 12, wherein the thixatropic gelatine carrier comprises: from about84% to about 95% vegetable oil selected from the group consisting ofsoybean oil, rapeseed oil, palm oil, and cotton seed oil; from about 1%to about 9% of a viscosity modifier selected from the group consistingof a glyceryl palmito stearate and glyceryl behenate; and from about 1%to about 15% of a surface active agent comprising polyglyceryl oleate.14. The soft gel capsule prepared by the process of claim 12, whereinthe thixatropic gelatine carrier is heated from about 27° C. to about30° C.
 15. The soft gel capsule prepared by the process of claim 12,wherein 30 to 100 mg of the Coenzyme Q10 are in each capsule.
 16. Thesoft gel capsule prepared by the process of claim 12, wherein themixture is cooled from about 23° C. to 28° C.
 17. The soft gel capsuleprepared by the process of claim 12, wherein 50 to 500 mg of thethixatropic gelatine carrier is in each capsule.
 18. A process ofmanufacturing a soft gel capsule comprising Coenzyme Q10, said processcomprising the steps of: (a) mixing a thixatropic gelatine carrier andCoenzyme Q10 to form a mixture; and (b) encapsulating the mixture in asoft gel capsule.
 19. The process of claim 18, wherein the thixatropicgelatine carrier comprises: from about 84% to about 95% vegetable oilselected from the group consisting of soybean oil, rapeseed oil, palmoil, and cotton seed oil; from about 1% to about 9% of a viscositymodifier selected from the group consisting of a glyceryl palmitostearate and glyceryl behenate; and from about 1% to about 15% of asurface active agent comprising polyglyceryl oleate.
 20. The process ofclaim 18, further comprising the step of heating the mixture from about27° C. to about 30° C.
 21. The process of claim 18, wherein 30 to 100 mgof the Coenzyme Q10 are in each capsule.
 22. The process of claim 18,wherein the mixture is cooled from about 23° C. to 28° C.
 23. Theprocess of claim 18, wherein 50 to 500 mg of the thixatropic gelatinecarrier is in each capsule.
 24. A process of manufacturing a soft gelcapsule comprising Coenzyme Q10, said process comprising the steps of:(a) stirring a thixatropic gelatine carrier until the thixatropicgelatine carrier is liquefied; (b) adding Coenzyme Q10 and anantioxidant to the liquefied carrier to form a mixture; and (c)encapsulating the mixture in a soft gel capsule.
 25. The process ofclaim 24, wherein the thixatropic gelatine carrier comprises: from about84% to about 95% vegetable oil selected from the group consisting ofsoybean oil, rapeseed oil, palm oil, and cotton seed oil; from about 1%to about 9% of a viscosity modifier selected from the group consistingof a glyceryl palmito stearate and glyceryl behenate; and from about 1%to about 15% of a surface active agent comprising polyglyceryl oleate.26. The process of claim 24, further comprising the step of heating thethixatropic gelatine carrier from about 27° C. to about 30° C. prior tothe addition of the Coenzyme Q10 and antioxidant.
 27. The process ofclaim 24, wherein 30 to 100 mg of the Coenzyme Q10 are in each capsule.28. The process of claim 24, wherein 10 to 100 mg of the antioxidant arein each capsule.
 29. The process of claim 28, wherein the antioxidant isvitamin E.
 30. The process of claim 24, wherein the mixture is cooledfrom about 23° C. to 28° C.
 31. The process of claim 24, wherein 50 to500 mg of the thixatropic gelatine carrier is in each capsule.